The differentiation of naive CD4+ T cells into mature T cells that produce either IL-4 or IFNgamma is controlled by IL-4 itself. If IL-4 is present at the time of priming, T cells develop into IL-4-producers while if it is absent they differentiate into IFNgamma producers. Using T cells from mice transgenic for genes encoding a T cell receptor specific for a cytochrome c peptide, the stability of cytokine-producing phenotypes was studied. After transgenic T cells were primed in vitro, they were transferred to syngeneic hosts, remained there for one month and then tested, after an in vitro "re-priming", for cytokine-producing phenotype. IL-4-producing capacity was stable but cells that had failed to produce IFNgamma initially could become IFNgamma-producing cells if re-primed in the absence of IL-4, implying that the regulation of production of the two cytokines is different and that the presence or absence of IL-4-production is a more reliable measure of the phenotype of activated CD4 cells than is IFNgamma-production. The source of the IL-4 that acts at the time of initial in vivo priming was sought. A set of CD4+, NK1.1+ T cells specific for CD-1 was shown to promptly produce IL-4 in response to in vivo activation. These cells appear to be diminished in number and function in two strains of mice, beta2- microglobulin knock out and SJL. Both strains of mice have defects in IgE and IL-4 production in response to polyclonal in vivo B cell activation, indicating the importance of CD4+, NK1.1+ T cells as a source of IL-4 at the outset of responses. The IL-4 receptor transduces signals mediating the function of the cytokine. Growth and differentiation are largely controlled by distinct domains of the cytosolic portion of the receptor. The region between amino acids 437 and 557 contains a region (the I4R motif) with a single tyrosine to which the substrate 4PS docks. This region is essential for IL-4-mediated growth. It also can mediate differentiation (i.e. induction of CD23 and germline Cepsilon transcripts as well as activation of STAT-6), but only to a small extent. By contrast, the region between amino acids 557 and 657 does not mediate phosphorylation of 4PS but induces CD23 and germline Cepsilon very efficiently. It contains three tyrosines; mutation of all 3 tyrosines ablates this activity but if any one of the tyrosines is not mutant, the region can still induce IL-4- mediated differentiation. Preliminary results indicate that the two domains interact and that this interaction results in inhibition of function.